Cerebellum最新文献

Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is a rare neurodegenerative disorder due to mutations in the SACS gene. While the typical phenotype is characterized by cerebellar ataxia, spasticity, and peripheral neuropathy, more reports are published of atypical and late-onset presentations, also lacking typical cerebellar signs of the disease, which can mimic Charcot-Marie-Tooth disease (CMT). We report a 58-year-old Chinese male with a 12-year history of progressive gait instability and lower limb weakness, who also exhibited retinal degeneration. Remarkably, in contrast to the majority of ARSACS patients, he had no significant spasticity, thus expanding the phenotypic spectrum. Genetic analysis identified a pathogenic compound heterozygous mutation in SACS: a novel frameshift variant (c.178del, p.Asp60ThrfsTer8) in exon 4, unreported in ClinVar, and a missense variant (c.4723 C > T, p.Arg1575Trp) in exon 10, documented in ClinVar with conflicting interpretations. The exceptionally late onset in this patient suggests that the c.178del frameshift may partially preserve sacsin function, thereby delaying disease manifestation. MLPA analysis excluded CMT1/HNPP-related rearrangements, confirming an ARSACS diagnosis. Familial segregation further supported autosomal recessive inheritance, emphasizing the importance of family screening. Given this, our case suggests a potential extended therapeutic window in late-onset ARSACS and may need to be included in future therapeutics efforts, emphasizing the importance of identifying such atypical forms. This observation highlights the importance of thorough genetic testing in achieving a correct diagnosis and providing treatment for patients with undiagnosed progressive ataxia.

Dysphagia is a frequent symptom of spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD), being associated with alterations in nutritional intake and hydration, as well as an increased risk of aspiration pneumonia. This study aims to evaluate the impact of self-perceived dysphagia and its relationship with quality of life in SCA3/MJD mutation carriers. 41 SCA3/MJD mutation carriers from the Azorean cohort were recruited. The Swallowing Quality-of-Life Questionnaire (SWAL-QOL), the Eating Assessment Tool (EAT-10), the Functional Oral Intake Scale (FOIS), the Volume-Viscosity Swallow Test (V-VST), the Scale for the Assessment and Rating of Ataxia (SARA), the Inventory of Non-Ataxia Signs (INAS), and the Activities of Daily Living (ADL) were applied. Dysphagia was confirmed in 40% SCA3/MJD patients, whose SWAL-QOL was significantly decreased when compared to participants without dysphagia (p = 0.001). As expected, SCA3/MJD carriers with worse SWAL-QOL showed a high risk of dysphagia (p < 0.01), a worse functional oral intake of food and liquids (p < 0.01) and more severe ataxia (p < 0.01). Additionally, high severity of dysphagia reported on the INAS scale, (p < 0.01) and high frequency of swallowing disorders, perceived by SCA3/MJD carriers (p < 0.01) were observed in SCA3/MJD carriers with worse SWAL-QOL. Our findings confirm that dysphagia negatively impacts the quality of life of SCA3/MJD carriers, highlighting the need for permanent support by specialized healthcare professionals during disease progression. Additionally, we recommend that SCA3/MJD carriers with a score of 1 or higher on both the INAS dysphagia item and the ADL swallowing item be referred for specialized healthcare support in swallowing disorders.

Spinocerebellar ataxia 1 (SCA1) is a rare autosomal dominant neurodegenerative disease characterized by impaired gait, coordination, and balance. SCA1 results from an expanded CAG repeat in the Atxn1 gene, inducing protein aggregation and ultimately leading to the degeneration of cerebellar Purkinje cells. Clinical studies have shown that gait impairments, such as changes in stride length (SL), stride time, and stance phase, are seen in patients with cerebellar diseases. The SCA1^154Q/2Q mouse model reflects the longitudinal progression of SCA1 in humans, displaying motor incoordination, muscle atrophy, and cerebellar Purkinje cell degradation. In this study, we aim to characterize the progression of gait impairments that arise in the SCA1^154Q/2Q mouse model. The DigiGait™ system, which utilizes ventral plane imaging technology, was used to track gait parameters in SCA^154Q/2Q mice, beginning at 7 weeks of age until 42 weeks. Our data revealed that SCA^154Q/2Q males exhibited decreasing gait speeds beginning weeks 15-16 (p < 0.05), and SCA^154Q/2Q females showed gait speed declining as early as 9 weeks (p < 0.05). A decrease in SL was also found; these emerged at different time points in SCA1^154Q/2Q mice, ranging from weeks 14 to 32. Our data also suggest that SCA1 mice have decreased loading speed in hindlimbs with lower MAX dA/dt values at weeks 30 and 40 in both males and females (p < 0.01). Our characterization of this model establishes a framework for sex- and age-related differences, as well as a timeline of various gait performance metrics, which provides a foundation to test the efficacy of novel therapeutics.

To investigate the characteristics of cross-sectional and longitudinal changes in cerebellar functional gradients in patients with temporal lobe epilepsy (TLE) and to explore the underlying molecular genetic mechanisms.This study included both cross-sectional and longitudinal phases. The cross-sectional study included 115 TLE patients and 75 healthy controls (HCs) and analyzed the cerebellar functional connectivity gradient using resting-state functional magnetic resonance imaging (rs-fMRI); the longitudinal study followed 29 TLE patients and 29 HCs and assessed the changes in the cerebellar functional connectivity gradient over a four-year period (44.24 ± 16.64 months). Gene expression data from the Allen Human Brain Atlas were used to analyze the association of differences in gradient changes with gene expression. (1) Both TLE patients and HCs showed typical functional cerebellar gradient patterns. (2) Cross-sectional analyses revealed that TLE patients had a contracted range of main cerebellar gradients and significantly higher gradient values in the default mode network (DMN). (3) Longitudinal analyses showed that cerebellar DMN gradients were initially abnormal in TLE patients at baseline（BL）; with disease progression, the DMN stabilized. (4) 151 genes associated with gradient differences were identified, and GO enrichment analysis mainly involved endocytosis, synaptic structure, metabolism, and ion channels. Protein interaction network analysis identified WASF1, RAC1 and MTG1 as key hub genes. This study provides initial evidence of dynamic changes in cerebellar functional gradients and their potential molecular correlates in TLE patients for the first time by functional magnetic resonance imaging gradient analysis, providing a new perspective for understanding the neuroplasticity of TLE.

Digital measures derived from wearable sensors are a promising approach for assessing motor impairment in clinical trials. Submovements, which are velocity curves extracted from time series data, have been successful in characterizing impaired movement during specific motor tasks as well as from natural behavior. In this study, we evaluate the influence of different limb movements on submovement kinematic properties. Individuals with ataxia (n = 70) and healthy controls (n = 27) wore inertial sensors on their wrists and ankles and performed five neurologically-relevant tasks-finger-nose, fast alternating hand movements (AHM), finger-chase, heel-stomping, and heel-shin. A common framework was applied to extract submovements from each task and eight submovement kinematic features were analyzed. Though submovement kinematic properties changed in response to disease severity, they were primarily influenced by motor task and direction of motion. Modeling experiments revealed that accounting for task and direction of motion improved estimation of ataxia severity; the best performing model accurately estimated clinician-administered ataxia ratings (r = 0.82, 95%CI: 0.77-0.86), and found the finger-chase task to be most informative of severity. Although there were differences across tasks, in general, individuals with ataxia had submovements with lower peak accelerations and more variable kinematics. Relationships between ataxia severity and submovement durations, distances, and peak velocities were more task dependent. These results demonstrate that a common submovement analysis approach can be used to estimate ataxia severity across a wide range of motor tasks and that estimation of severity can be improved by accounting for movement type and direction of motion.

Ataxias are a group of neurologic disorders, with heterogeneous clinical and genetic presentation and with a challenging diagnostic approach that navigates through the neuroimage field. Typical clinical features of ataxias include variable degrees of cerebellar ataxia, as a pure clinical picture or associated with other neurologic or extra neurological symptoms (cognitive impairment, epilepsy, other movement disorders, abnormal ocular movements, systemic symptoms). Neuroimaging plays an important role in the characterization of patients with ataxia. Despite the development of genetics and neuroimaging, some cases remain with no diagnosis. This review proposes a didactic investigation approach for ataxias based on three main magnetic resonance imaging features: a) ataxias without cerebellar atrophy; b) ataxias with pure cerebellar atrophy or olivopontocerebellar atrophy; and c) ataxias with specific imaging features. A comprehensive review of peer-reviewed articles on neuroimaging in diseases associated with cerebellar ataxia was conducted through a search in PubMed and SciELO. For each topic, we discuss the possible diagnosis and suggest a guided investigation. The classification of cerebellar ataxias into distinct categories-based on the presence or absence of cerebellar atrophy and specific neuroradiological features-profoundly enhances the diagnostic approach to these complex disorders.

Reward processing involves several components, including reward anticipation, cost-effort computation, reward consumption, reward sensitivity, and reward learning. Recent research has highlighted the cerebellum's role in reward processing. This study aimed to investigate the effects of cerebellar stimulation on reward processing using high-definition transcranial direct current stimulation (HD-tDCS). In this single-blind, randomized, sham-controlled study, 63 healthy adults received either active (N = 31) or sham (N = 32) 1.7 mA HD-tDCS targeting the right posterior cerebellum for 20 minutes. Reward processing was assessed before and after stimulation using the Monetary Incentive Delay (MID) Task, the Effort-Expenditure for Rewards (EEfRT-Adaptive) Task, and the Probabilistic Stimulus Selection Task (PST). Results showed that the active stimulation group preserved anticipatory and consummatory pleasure in response to high rewards in the MID task, whereas the sham group exhibited a decline in these measures from pre-test to post-test. The active stimulation group had enhanced reward sensitivity in the EEfRT-adaptive task. HD-tDCS appeared to influence the reward learning rate in the PST, although this effect was moderated by participants' emotional state. Our study provides preliminary evidence that HD-tDCS targeting the cerebellum can effectively modulate multiple facets of reward processing. Cerebellar stimulation may have therapeutic potential for psychiatric patients with impaired reward processing.

Multiple system atrophy (MSA) is a progressive, adult-onset neurodegenerative disorder involving autonomic failure, cerebellar ataxia, and parkinsonism. Patients often require invasive interventions, such as gastrostomy or tracheostomy, and sudden death is common. This study aimed to elucidate patterns of invasive treatment and identify risk factors for tracheostomy or sudden death within 5 years of onset. In total, 214 patients diagnosed with MSA between November 2014 and October 2024 across 66 institutions in Hokkaido were enrolled in the Hokkaido Rare Disease Consortium for MSA (HoRC-MSA). Patients were grouped by clinical course and interventions. We analyzed use of invasive procedures, including enteral nutrition via gastrostomy, enterostomy, esophagostomy, nasogastric tube insertion, central venous nutrition, tracheostomy, and ventilator support. Multivariable analyses were performed to compare patients with and without early critical events, defined as tracheostomy or sudden death within 5 years of disease onset. Invasive procedures were performed in 63.1% of patients. Patients receiving enteral nutrition and tracheostomy had prolonged survival. Early events correlated with older onset age (mean, 65.9 years), orthostatic hypotension, stridor, and an elevated apnea-hypopnea index (median, 32.45). Patients with preserved activities of daily living (ADL) in the Unified MSA Rating Scale part Ⅳ also had an increased risk of early critical events. Autonomic dysfunction, sleep-disordered breathing, and vocal cord impairment predict key risk factors for early mortality in patients with MSA. Monitoring is necessary, regardless of preserved ADL. The impact of invasive interventions on quality of life should be further explored.

Although intensive rehabilitation has achieved short-term benefits in patients with spinocerebellar degeneration, long-term outcomes of periodic intervention remain unclear, particularly in patients with pure spinocerebellar ataxia types 6 (SCA6) and 31 (SCA31). To investigate the longitudinal effects of annual intensive rehabilitation on ataxic symptoms and balance function in patients with pure cerebellar type SCA6 and SCA31. Seven patients with genetically confirmed SCA6 or SCA31 participated in annual 4-week intensive rehabilitation programmes. Each programme consisted of daily physical therapy, occupational/speech therapy, and self-directed balance training. The participants were assessed annually at pre-intervention, post-intervention, and the 6-month follow-up using the Scale for the Assessment and Rating of Ataxia (SARA) and Balance Evaluation Systems Test (BESTest). Changes were analysed using linear mixed-effect models. SARA scores were stable, indicating slower progression than the expected natural history, through year 6, with significant improvement observed post-intervention in year 2 (p = 0.04). Significant deterioration occurred at year 7 based on pre-intervention scores (p = 0.01), suggesting prolonged sustained benefits for coordination. The BESTest scores revealed an earlier decline, with significant deterioration from year 3 (p = 0.04), which progressed until year 7 (p < 0.01). Annual intensive rehabilitation effectively slowed the progression of ataxic symptoms (SARA) for up to six years, while balance function (BESTest) showed a significant decline from the third year. These findings indicate that an annual rehabilitation schedule is valuable for maintaining coordination but may be insufficient to prevent the progressive decline of balance function in patients with pure cerebellar ataxia.

Spinocerebellar ataxia type 27B (SCA27B), caused by GAA repeat expansions in FGF14, is an increasingly recognized form of late-onset cerebellar ataxia. However, early diagnosis remains challenging due to mild or absent cerebellar motor signs and often normal brain magnetic resonance imaging (MRI). Oculovestibular abnormalities, although prevalent, are frequently overlooked and not captured by standard clinical scales such as the Scale for the Assessment and Rating of Ataxia (SARA). This study aimed to perform a detailed and dedicated evaluation of vestibulo-ocular function in patients with SCA27B, and to develop a practical diagnostic framework that highlights the most prevalent findings and their anatomical correlates. We retrospectively analyzed 20 patients with genetically confirmed SCA27B who underwent structured bedside and quantitative neuro-visual assessments, including video-oculography (VOG) and video head impulse testing (vHIT). As a comparison group, we included patients with genetically confirmed SCA1, SCA2, SCA3, SCA6, and SCA8, who had undergone the same VOG protocol at our center. All SCA27B patients exhibited cerebellar ocular motor abnormalities, including downbeat, gaze-evoked, and rebound nystagmus. Compared to other SCAs, spontaneous and positional downbeat nystagmus was significantly more frequent in SCA27B (p < 0.001), whereas gaze-evoked and rebound nystagmus and impaired smooth pursuit occurred at similar rates, particularly in SCA6, which showed a partially overlapping profile. Quantitative vHIT revealed bilateral vestibular hypofunction, with lower vestibular-ocular reflex (VOR) gain most pronounced in the posterior canals (mean VOR gain: 0.44), followed by anterior (0.54) and horizontal canals (0.83; p < 0.001). Brain MRI was normal in two-thirds of patients, and SARA scores indicated only mild ataxia, underscoring the diagnostic limitations of conventional tools. Our results emphasize the value of oculovestibular evaluation as a sensitive disease marker and support its integration into future composite diagnostic scales for cerebellar ataxias.Trial Registration Information: Not applicable (retrospective study).